398: Premature termination of a prospective, open label, randomized, multicenter study of sirolimus to replace calcineurin inhibitors (CNI) in a standard care regimen of CNI, MMF and corticosteroids early after heart transplantation

Hunt, Judson; Bedáňová, Helena; Starling, Randall; Rábago, Gregorio; Banner, N.R.; Kobashigawa, J.A.; Keogh, Anne; Kormos, Robert L.; Mehra, Mandeep R.; Wahlers, T; Noeldeke, Jana

doi:10.1016/j.healun.2006.11.419

Cited by 29 publications

(16 citation statements)

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“…Acute rejection in patients converting to CNI-free, sirolimus-based immunosuppression regimens has come under scrutiny, particularly since the premature termination of the Heart Spare-the-Nephron trial in 2006 (18). That trial was halted because of an increased incidence of grade IIIA rejection episodes in the group converted to sirolimus (four of seven patients).…”

Section: Discussionmentioning

confidence: 99%

Randomized Controlled Trial of Sirolimus Conversion in Cardiac Transplant Recipients With Renal Insufficiency

Zuckermann

Keogh

Crespo-Leiro

et al. 2012

American Journal of Transplantation

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Clinical Trials. gov identifier number: NCT00369382This randomized, comparative, multinational phase 3b/4 study of patients 1-8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40-90 mL/min/1.73m 2 were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent-to-treat analysis showed the 1-year adjusted mean change from baseline in creatinine clearance (Cockcroft-Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. −1.4 mL/min/1.73 m 2 , respectively; p = 0.004). By on-therapy analysis, values were +4.7 and -2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment-emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.

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Section: Discussionmentioning

confidence: 99%

Randomized Controlled Trial of Sirolimus Conversion in Cardiac Transplant Recipients With Renal Insufficiency

Zuckermann

Keogh

Crespo-Leiro

et al. 2012

American Journal of Transplantation

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“…Thus, immunosuppression based on an mTOR inhibitor and early CNI withdrawal in de novo heart transplant patients has been considered, but caution due to concerns about side effects has meant that experience is limited to a few observational studies of everolimus or sirolimus with CNI avoidance (12,14). The only randomized trial of de novo heart transplant recipients to date, in which sirolimus was administered with CNI withdrawal, was terminated prematurely due to side effects (15). Thus, the optimal strategy for use of everolimus, and for mTOR inhibitors in general, may not yet have been found in heart transplantation.…”

Section: Introductionmentioning

confidence: 99%

Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal in Heart Transplant Recipients: A Randomized Trial

Andreassen

Andersson

Gustafsson

et al. 2014

American Journal of Transplantation

123

118

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“…However, the study was discontinued after inclusion of 15 patients because of an unexpected high incidence of rejection in the CNI withdrawal arm. 16 The study raised concerns that CNI withdrawal early after HT may be associated with an increased risk of rejection; thus, being more feasible in patients late after HT. This strategy has turned out to be safe and effective in several observational studies by improving serum creatinine after CNI withdrawal up to 25%.…”

Section: Discussionmentioning

confidence: 99%

Renal Recovery After Conversion to an Everolimus-Based Immunosuppression in Early and Late Heart Transplant Recipients: A 12-Month Analysis

Michel

Bigdeli²,

Hagl³

et al. 2013

Exp Clin Transplant

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Objectives: Calcineurin inhibitor-induced nephrotoxicity reduces long-term patient survival after heart transplant. Proliferation signal inhibitors, in combination with or replacing calcineurin inhibitors, may preserve or improve renal function. We evaluated the effect of calcineurin inhibitor-reduction and withdrawal in everolimus-based immunosuppression on renal function after a heart transplant. Materials and Methods: Twenty-four patients with creatinine clearance < 1 mL/s (60 mL/min) were switched from tacrolimus and mycophenolate mofetil to low-dose tacrolimus/everolimus if their heart transplant was ≤ 1 year ago (group 1, n=13) and to everolimus/mycophenolate mofetil if their heart transplant was > 1 year ago (group 2, n=11). Serum creatinine levels and calculated creatinine clearance were analyzed up to 12 months after conversion. Results: The switch in immunosuppression was associated with a significant decrease/increase of serum creatinine/creatinine clearance in both groups between baseline and month 12 (group 1, creatinine, 221.0 ± 70.7 to 159.1 ± 44.2 µmol/L (2.5 ± 0.8 to 1.8 ± 0.5 mg/dL); creatinine clearance, 0.75 ± 0.45 to 1.01 ± 0.50 mL/s (45.1 ± 26.7 to 60.5 ± 29.7 mL/min) (P < .01 each); group 2, creatinine, 247.5 ± 79.6 to 159.1 ± 44.2 µmol/L (2.8 ± 0.9 to 1.8 ± 0.5 mg/dL), creatinine clearance, 0.57 ± 0.23 to 0.93 ± 0.33 mL/s (34.1 ± 13.8 to 55.7 ± 19.6 mL/min) [P < .05 each]) with no significant group difference in the creatinine and the creatinine clearance levels after switching. No acute rejections or deaths occurred during the 12-month follow-up. Four patients (36.4%) from group 2 and 1 patient (7.7%) from group 1 discontinued everolimus because of adverse events. Conclusions: Everolimus allows calcineurin inhibitorreduction and withdrawal after heart transplantion resulting in improved renal function. However, adverse effects are common and lead to a high reconversion rate.

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398: Premature termination of a prospective, open label, randomized, multicenter study of sirolimus to replace calcineurin inhibitors (CNI) in a standard care regimen of CNI, MMF and corticosteroids early after heart transplantation

Cited by 29 publications

References 0 publications

Randomized Controlled Trial of Sirolimus Conversion in Cardiac Transplant Recipients With Renal Insufficiency

Randomized Controlled Trial of Sirolimus Conversion in Cardiac Transplant Recipients With Renal Insufficiency

Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal in Heart Transplant Recipients: A Randomized Trial

Renal Recovery After Conversion to an Everolimus-Based Immunosuppression in Early and Late Heart Transplant Recipients: A 12-Month Analysis

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